Pediatric Hodgkin Lymphoma...Summary of Recently Evaluated First-Line Treatment Trials in Pediatric Classical Hodgkin Lymphoma Study Risk Design No. Chemotherapy Radiation Key Findings

Pediatric Hodgkin LymphomaChristine Mauz-Körholz, Monika L. Metzger, Kara M. Kelly, Cindy L. Schwartz, Mauricio E. Castellanos,Karin Dieckmann, Regine Kluge, and Dieter Körholz

Christine Mauz-Körholz and DieterKörholz, Martin-Luther-University Medi-cal Center, Halle, Germany; Monika L.Metzger, St Jude Children’s ResearchHospital, Memphis, TN; Kara M. Kelly,Columbia University Medical Center,New York, NY; Cindy L. Schwartz, MDAnderson Cancer Center, Houston, TX;Mauricio E. Castellanos, Unidad Nacio-nal Oncologia Pediatrica, GuatemalaCity, Guatemala; Karin Dieckmann,Medical University of Vienna, Vienna,Austria; and Regine Kluge, University ofLeipzig, Leipzig, Germany.

Published online ahead of print atwww.jco.org on August 24, 2015.

Both C.M.-K. and M.L.M. contributedequally to this work.

Authors’ disclosures of potentialconflicts of interest are found in thearticle online at www.jco.org. Authorcontributions are found at the end ofthis article.

Corresponding author: Christine Mauz-Körholz, MD, Universitätsklinik undPoliklinik, für Kinder- und Jugendme-dizin, der Martin-Luther-UniversitätHalle-Wittenberg, Ernst-Grube-Straße40, 06120 Halle (Saale), Germany;e-mail: [email protected].

© 2015 by American Society of ClinicalOncology

0732-183X/15/3327w-2975w/$20.00

DOI: 10.1200/JCO.2014.59.4853

A B S T R A C T

Hodgkin lymphoma (HL) is one of the most curable pediatric and adult cancers, with long-termsurvival rates now exceeding 90% after treatment with chemotherapy alone or combined withradiotherapy (RT). Of note, global collaboration in clinical trials within cooperative pediatric HLstudy groups has resulted in continued progress; however, survivors of pediatric HL are at high riskof potentially life-limiting second cancers and treatment-associated cardiovascular disease. Overthe last three decades, all major pediatric and several adult HL study groups have followed theparadigm of response-based treatment adaptation and toxicity sparing through the reduction orelimination of RT and tailoring of chemotherapy. High treatment efficacy is achieved usingdose-dense chemotherapy. Refinement and reduction of RT have been implemented on the basisof results from collaborative group studies, such that radiation has been completely eliminated forcertain subgroups of patients. Because pediatric staging and response criteria are not uniform,comparing the results of trial series among different pediatric and adult study groups remainsdifficult; thus, initiatives to harmonize criteria are desperately needed. A dynamic harmonizationprocess is of utmost importance to standardize therapeutic risk stratification and responsedefinitions as well as improve the care of children with HL in resource-restricted environments.

J Clin Oncol 33:2975-2985. © 2015 by American Society of Clinical Oncology

INTRODUCTION

Since the late 1970s, pediatric Hodgkin lymphoma(HL) has been treated succesfully in cooperativegroup trials.1-5 Initially, high-dose extended-fieldradiation proved to be effective in adults with early-stage disease, whereas chemotherapy combinationsof mechlorethamine, vincristine, procarbazine,and prednisone as well as doxorubicin, bleomy-cin, vinblastine, and dacarbazine (ABVD) orcombined-modality treatment were reserved foradvanced disease.6 These treatments were modi-fied for children by reducing radiation dose andfield size and relying on chemotherapy across alldisease stages. With increasing concerns aboutaging survivors of pediatric cancer,7-9 generaltreatment approaches for the disease have changed.The use of alkylators has been reduced and thenumber and composition of chemotherapy cycleshave been adapted to individual risk factors.2-4,10,11

Radiotherapy (RT) has been limited to involvedfields and doses adapted to disease risk.1,4 Theconcept of using early response to tailor therapyin dose-dense regimens has been refined.11 Pro-carbazine has been gradually eliminated to reducethe risk of infertility, and etoposide and doxoru-bicin substituted to reduce the cumulative alky-lating agent dose.11-14

For more than 30 years, collaborations amongcooperative groups globally have led to varied treat-ment approaches for pediatric HL. North Americanand most European study groups4,13,15-24 have fa-vored combined-modality treatment approaches,whereas Central and South American groups25-27

have initially pursued chemotherapy-only regimens(Table 1). Since 2005, most European groups havebeen working together under the umbrella of theEuropean Network for Pediatric Hodgkin Lym-phoma (EuroNet-PHL). The Pediatric OncologyGroup and Children’s Cancer Group have mergedto form the Children’s Oncology Group (COG), andthe Asociación de Hemato-Oncología Pediátrica deCentro América (AHOPCA) and the Grupo Argen-tino de Tratamiento de la Leucemia Aguda (GATLA)have also recently agreed to implement the same pro-tocol with the prospect of more South American sitesto follow.

There is an increasing need to harmonize thestaging and response criteria (eg, [18F]fluoro-deoxy-glucose [FDG] –positron emission tomography[PET] response definitions) for pediatric HL, be-cause risk classifications and treatment groupallocations differ substantially among cooperativegroups—it is important to compare the treatmentphilosophies for adult and pediatric HL. The inter-national collaboration in pediatric HL has gained an

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interactive forum with the Children, Adolescent and Young Adult HL(CAYAHL) symposia, which are held every 3 years. Study groups fromEurope, the Americas, Asia, Australasia, Africa, and the Middle Eastare using this platform to share their clinical experiences.27a,42-47 TheStaging Evaluation and Response Criteria Harmonization (SEARCH)effort for CAYAHL was also initiated through this platform.48,49

Treatment for pediatric HL has focused on minimizing toxicityand late effects and preserving high cure rates. In this review, wediscuss the collaborative clinical trials on pediatric HL and their strat-egies to reduce or eliminate RT. We also review the standardization ofFDG-PET evaluation definitions, harmonization of treatment resultsfrom various study groups, and new agents under investigation inpediatric HL.

OBJECTIVES OF CONTEMPORARY COLLABORATIVECLINICAL TRIALS

Contemporary pediatric HL trials have aimed to eliminate the go-nadotoxic alkylator procarbazine, introduce dose-dense chemother-apy cycles, and evaluate response-based treatment adaptations (Table2 and Appendix Table A1, online only). In low- and middle-incomecountries, the choice of treatment approach is driven by factors differ-ent from those seen in European and North American groups, but thiswill possibly also provide insights into response adaptation.

Elimination of Procarbazine and Introduction of

Dose-Dense Chemotherapy Regimens

The Deutsche Arbeitsgemeinschaft für Leukämieforschung(DAL) and the German Society of Pediatric Oncology andHematology–Hodgkin’s Disease (GPOH-HD) have made several at-tempts to eliminate procarbazine from the vincristine, procarbazine,prednisone, and doxorubicin (OPPA) and cyclophosphamide, vin-cristine, procarbazine, prednisone (COPP) cycles to reduce the risk ofmale infertility and preserve high cure rates. The pivotal DAL-90 trialdemonstrated that etoposide can successfully replace procarbazine inthe OPPA induction cycle, thereby reducing the risk of male infertilityin early-stage HL.4 In the GPOH-HD-2002 trial, a completelyprocarbazine-free regimen was given to boys by replacing procarba-zine with dacarbazine to create the novel regimen vincristine, etopo-side, prednisone, and doxorubicin–cyclophosphamide, vincristine,prednisone, and dacarbazine (OEPA-COPDAC). Outcomes of boystreated with the OEPA-COPDAC regimen were comparable to thoseof girls receiving the OPPA-COPP standard treatment (Table 2).13 Inthe GPOH-HD-2002/VECOPA pilot trial, another dose-intensiveprocarbazine-free regimen comprising vinblastine, etoposide, cyclo-phosphamide, vincristine, prednisone, and doxorubicin was exploredin the intermediate- and high-risk male patient groups.14 In contrastto these gender-stratified trials, the effect of OEPA-COPDAC versusOEPA-COPP is currently being studied in the European Network forPediatric Hodgkin Lymphoma (EuroNet-PHL) –C1 trial (Appendix

Table 1. Collaborative Pediatric Hodgkin Lymphoma Groups

Group Radiotherapy RCT

North American collaborationsSt Jude–Stanford–Dana Farber28,29,30,31,32 RA: anatomic response; IFRT for all patients (all risk groups) in non-CR NoPediatric Oncology Group (POG)2,11,33-35 RA: metabolic response (gallium scan); IFRT for all patients in

nonmetabolic CR; IFRT randomization for all patients in metabolicCR after all chemotherapy

Yes

Children’s Cancer Group (CCG)3,36,37 RA: anatomic response; IFRT for all patients in non-CR; IFRTrandomization for all patients in CR at early response assessment

Yes

Children’s Oncology Group (COG)38,39 RA: anatomic response; IFRT for intermediate-risk patients in non-CR;IFRT randomization for intermediate-risk patients in CR at earlyresponse assessment

Yes

European collaborationsGerman Austrian Pediatric Oncology Hematology Society-Hodgkin Study

Group (DAL/GPOH-HD)4,14-16Yes, IFRT for all patients, all risk groups No

German Pediatric Oncology Group (GPOH-HD)13,17,18 RA: anatomic response; IFRT for all patients, all risk groups in non-CR NoAssociazione Italiana Ematologia Oncologia Pediatrica (AIEOP)19 No, chemotherapy-only regimen NoPolish Pediatric Leukemia/Lymphoma Study Group (PPLLSG)20 Yes, IFRT for all patients, all risk groups NoSociété Française de Lutte contre les Cancers et Leucémies de l’Enfant

et de l’Adolescent (SFCE)21Yes, IFRT for all patients in the low- and intermediate-risk groups No

United Kingdom Children’s Cancer and Leukaemia Group (CCLG)22-24 Yes, RT only for patients in clinical stage I and those with bulkydisease; No, chemotherapy-only regimens

No

European Network for Pediatric Hodgkin Lymphoma (EuroNet-PHL)†40 RA: metabolic (PET) response; IFRT only for patients (all risk groups)with early response–positive PET

Yes�

Latin American collaborationsAsociación de Haemato-Oncología Pediátrica de Centro América

(AHOPCA)†25,26RA: anatomic response; IFRT for low- and intermediate-risk patients in

non-CR; No, chemotherapy-only regimen for high-risk patientsNo

Grupo Argentino de Tratamiento de la Leucemia Aguda (GATLA)27 No, chemotherapy only regimen (randomized) for favorable-riskpatients Yes, IFRT for high-risk patients

Yes

Abbreviations: CR, complete response; IFRT, involved-field radiotherapy; PET, positron emission tomography; RA, response adaptation; RCT, randomizedcontrolled trial.

�Chemotherapy randomization.†Participating countries in EuroNet-PHL: Austria, Belgium, Czech Republic, Denmark, France, Germany, Ireland, Italy, the Netherlands, Norway, Poland, Portugal,

Slovakia, Slovenia, Spain, Sweden, Switzerland, United Kingdom, Australia, Israel, and New Zealand.‡Participating countries in AHOPCA: Guatemala, El Salvador, Honduras, Nicaragua, Dominican Republic, and Costa Rica.

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Table A1).40 In this trial, all patients receive OEPA, but patients in theintermediate- and high-risk groups—treatment groups 2 and 3—arerandomly assigned to receive COPP or COPDAC to test whetherequivalent results can be achieved with a less gonadotoxicprocarbazine-free regimen.

Similarly, the Pediatric Oncology Group developed a dose-denseprocarbazine-free regimen comprising doxorubicin, bleomycin, vin-cristine, and etoposide and prednisone and cyclophosphamide.11 Inthe original P9425 and P9426 trials, patients were randomly assignedto receive the topoisomerase inhibitor dexrazoxane as a cardiopulmo-

nary protectant during treatment.50 Early evaluation of dexrazoxane-associated second malignant neoplasms suggested an increased riskfor secondary acute myeloid leukemia (sAML) or myelodysplasticsyndrome, with 6 of 8 patients in the dexrazoxane arm developingAML/myelodysplastic syndrome and 2 patients developing solid tu-mors. The 4-year cumulative incidence rate of any secondary malig-nancy was 2.55% for patients in the dexrazoxane arm versus 0.85% forthose in the nondexrazoxane arm (P � .06). Subsequent COG trialshave therefore discouraged the use of dexrazoxane, and the risk ofsAML in the nondexrazoxane arm seems to be low. In the

Table 2. Summary of Recently Evaluated First-Line Treatment Trials in Pediatric Classical Hodgkin Lymphoma

Study Risk Design No. Chemotherapy Radiation Key Findings

Children’s Oncology Group (COG)Trials

AHOD003138 Intermediate Randomized with earlyresponse–basedtherapy tailoring

1,369 RER: 4 � ABVE-PC

RER/CR: � 21 Gy IF Early responseassessmentsupported omitting RTin RERs with CR andaugmentingchemotherapy inSERs with PET-positive disease.

RER � CR: 21 GyIF

2002-2009 305 SER: 4 � ABVE-PC � 2 � DECA

SER: 21 Gy IF

German Pediatric OncologyHematology HodgkinDisease (GPOH-HD) StudyGroup

GPOH-HD-200213 Low (TG1) Nonrandomized,gender-stratified,response-based RTallocation

195 Girls: 2 � OPPA CR: none Radiation can safely beomitted in patientswho achieve CR aftertwo cycles of OPPAor OEPA.

2002-2005 Boys: 2 � OEPA � CR: 19.8 Gy IF

Intermediate(TG2)

Nonrandomized,gender stratified

139 Girls: 2 � OPPA �2 � COPP

19.8 Gy IF OEPA-COPP and OEPA-COPDAC areequivalent regimensin intermediate-riskpatients.

Boys: 2 � OEPA �2 � COPDAC

High (TG3) Nonrandomized,gender stratified

239 Girls: 2 � OPPA �2 � COPP

19.8 Gy IF OEPA-COPP and OEPA-COPDAC areequivalent regimensin high-risk patients.

Boys: 2 � OEPA �2 � COPDAC

St Jude–Stanford–Dana FarberConsortium

HOD9928 Low Nonrandomized,response-based RTallocation

88 4 � VAMP CR: none Patients with highlyfavorable features cansafely be treatedwithout alkylators andRT if they achieve CRafter two cycles ofVAMP.

2000-2009 � CR: 25 Gy IF

AHOPCA consortiumLH 199926 Favorable Nonrandomized,

response-basedchemotherapyallocation

94 6 � COPP � 4 �COPP/ABV

None Patients with � CR aftertwo cycles of COPPreceived additionalfour cycles of COPP/ABV.

1999-2004 Unfavorable Nonrandomized,chemotherapyallocation

118 8 � COPP/ABV None All patients receivedeight cycles ofCOPP/ABV.

NOTE. All drug doses are displayed in cumulative doses per cycle.Abbreviations: ABVE-PC, doxorubicin 50 mg/m2, bleomycin 15 IU/m2, vincristine 2.8 mg/m2, etoposide 375 mg/m2, prednisone 280 mg/m2, cyclophosph-

amide 800 mg/m2; AVPC, doxorubicin 50 mg/m2, vincristine 2.8 mg/m2, prednisone 280 mg/m2, cyclophosphamide 1,200 mg/m2; COPDAC: cyclophosph-amide 1,000 mg/m2, vincristine 3.6 mg/m2, prednisone 600 mg/m2, dacarbazine 750 mg/m2; COPP, cyclophosphamide 1,000 mg/m2, vincristine 3.6 mg/m2,prednisone 600 mg/m2, procarbazine 1,500 mg/m2; COPP/ABV, cyclophosphamide 600 mg/m2, vincristine 1.5 mg/m2, prednisone 560 mg/m2, procarbazine700 mg/m2, doxorubicin 30 mg/m2, vinblastine 6 mg/m2, bleomycin 10 IU/m2 ; COPP (AHOPCA), cyclophosphamide 600 mg/m2, vincristine 1.5 mg/m2,prednisone 560 mg/m2, procarbazine 1,400 mg/m2; CR, complete response; DECA, dexamethasone 20 mg/m2, etoposide 200 mg/m2, cisplatin 60 mg/m2,cytarabine 6,000 mg/m2; IF, involved field; OEPA, vincristine 5.4 mg/m2, prednisone 900 mg/m2, etoposide 625 mg/m2, doxorubicin 160 mg/m2; OPPA,vincristine 4.5 mg/m2, prednisone 900 mg/m2, procarbazine 1,500 mg/m2, doxorubicin 160 mg/m2; PET, positron emission tomography; RER, rapid earlyresponder; RT, radiotherapy; SER, slow early responder; VAMP, vinblastine 12 mg/m2, doxorubicin 50 mg/m2, methotrexate 40 mg/m2, prednisone560 mg/m2.

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GPOH-HD-2002 trial, none of the 287 boys receiving the etoposide-containing regimen developed sAML, whereas 1 girl who did notreceive etoposide developed sAML.13 The Stanford V regimen ad-opted by the St Jude–Stanford–Dana Farber consortium is acombined-modality strategy originally developed by an adult studygroup51 in which a 12-week, multiagent, non–cross-resistant dose-dense regimen combined with involved-field RT (IFRT) was given topatients with intermediate- and advanced-stage HL (Appendix TableA1).52 Mature long-term data from Stanford V show a low risk ofsAML for patients administered this regimen, with none of the 256patients observed for more than 5 years developing sAML.53 In thisregimen, low cumulative doses of alkylating agents also improve theprospects of fertility.

Response Adaptation to Reduce or Eliminate RT

In HL trials on adults, RT remains an essential component oftreatment, especially for patients with early-stage disease who aretreated with ABVD chemotherapy. In contrast, pediatric HL studygroups balance the risk-benefit ratio differently. Althoughcombined-modality approaches usually provide high responserates with event-free survival (EFS) rates of approximately 90%,the risk of radiation-induced second cancers, cardiovascular dis-ease, and thyroid dysfunction in survivors of pediatric HL increasesthroughout their lifetime.8,9,54,55

The CCG trial C5942, one of the first pediatric trials aimed ateliminating RT, randomly assigned patients who had achieved ana-tomic complete response (CR) after completion of COPP/ABV hybridchemotherapy to either IFRT or no further therapy.36 The 10-year EFSrate, but not the overall survival (OS) rate, was significantly loweramong those treated with chemotherapy alone.56 However, this trialwas compromised by the use of less intensive chemotherapy than isused in most contemporary trials. Despite international collabora-tions, randomized clinical trials to evaluate the added benefit of RTremain challenging in pediatric HL because the limited number ofpatients makes it difficult to achieve statistical power. Therefore, mostcollaborative consortia are adopting a response-based RT delivery inwhich patients with an early favorable response to chemotherapy arechosen to undergo reduced RT or forgo it completely. The St Jude–Stanford–Dana Farber consortium evaluated response-based radia-tion in low-risk patients treated with vinblastine, doxorubicin,methotrexate, and prednisone (VAMP) chemotherapy. RT was ad-ministered only to patients who did not achieve an early, that is, aftertwo cycles of VAMP, anatomic and metabolic CR. The 5-year EFSrates of patients treated with four cycles of VAMP chemotherapy aloneand four cycles of VAMP chemotherapy plus 25.5 Gy IFRT28 weresimilar (Table 2).

In the GPOH-HD95 trial, RT was omitted in patients achievinganatomic CR after OEPA-COPP chemotherapy. The 10-yearprogression-free survival (PFS) rate for patients with intermediate-and advanced-stage disease (69% and 83%, respectively) was signifi-cantly lower for patients with a CR than for those who did not achievea CR and received IFRT. The PFS rates for patients with low-riskdisease that did and did not receive RT were similar.18 However, theOS rates of patients in all treatment groups were excellent and similar.Thus, assessment by anatomic response at completion of chemother-apy might not be adequate to identify patients who can receive re-duced RT without increasing the risk of relapse.

Among more contemporary pediatric trials, moderately dose-intensified chemotherapy regimens have facilitated RT reductionstrategies. Early response assessment after more intensive doxorubi-cin, bleomycin, vincristine, and etoposide and prednisone and cyclo-phosphamide chemotherapy in the COG AHOD0031 trial identified agroup of early responders for whom RT could be eliminated withoutcompromising long-term survival.38 This study enrolled 1,712 eligiblepatients and is the only random assignment phase III trial to assesstreatment stratification on the basis of early response. The EFS rate ofrapid early responders with an anatomic response of more than 80%after two cycles and a negative gallium 67 or FDG-PET scan at the endof all chemotherapy did not improve with the addition of RT. Simi-larly, preliminary results of the COG AHOD0431 trial for low-risk HLseem to have identified a group of very early responders (negative PETscan after one cycle) who may have an improved outcome withoutadjuvant RT.57 It is therefore not surprising that response assessmenthas evolved, and, currently, more value is placed on functional assess-ment by PET scans.

Recently, EuroNet-PHL completed its first large cooperative trial(EuroNet-PHL-C1) on the basis of the GPOH-HD chemotherapybackbone (OEPA-COPP/COPDAC) in which more than 2,100 pa-tients were recruited. IFRT was administered only to patients whosePET scans were positive after two initial OEPA cycles. Preliminaryresults suggest that this strategy is feasible to identify patients who canhave good long-term survival without RT.

Table 3 summarizes the most recent strategies used to reduce oreliminate RT in pediatric and adult HL trials. Although in seminalpediatric trials early response adaptation was a key feature incombined-modality approaches for eliminating RT in all risk groups,elimination of RT is the main objective only in adult patients withadvanced-stage HL. RT remains a standard treatment element in adultpatients with early- and intermediate-stage disease.58-60 Essentially,more intensive chemotherapy might be required to balance the elim-ination of RT. Table 4 presents strategies for the systematic reductionof radiation dose and field size as well as for omitting RT in patientswith early-stage classical HL (cHL). The table highlights the develop-ment of RT regimens over eight consecutive trials of the DAL/GPOH-HD/EuroNet-PHL groups.

Rationale for Therapy Approach and Response

Adaptation in Low- and Middle-Income Countries

In many low- and middle-income countries, health care institu-tions that lack reliable access to radiation facilities, trained personnel,and diagnostic imaging modalities have traditionally preferredchemotherapy-only approaches. Earlier chemotherapy-only trialsprescribed six to 12 cycles of mechlorethamine, vincristine, procarba-zine, and prednisone61,62; hybrid therapies containing alkylatingagents, such as chlorambucil, vinblastine, procarbazine, and predni-sone63; or alternating non–cross-resistant regimens, such as COPP/ABVD,64,65 COPP/ABV hybrids,66,67 or their combinations withoutalkylating chemotherapy agents.68 GATLA evaluated chemotherapyalone versus combined-modality therapy prospectively for early-stagedisease (stages I and II). The addition of IFRT improved the disease-free survival rates for patients with more than two involved nodalareas, bulky peripheral (� 5 cm) adenopathy, bulky mediastinal ade-nopathy, or advanced-stage disease.69 The next GATLA trial foundsimilar EFS rates for patients with favorable prognosis who wererandomly assigned to three or six cycles of chemotherapy; the results

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of the chemotherapy-only approach were not different from thecombined-modality strategy of their previous trial.70

The Central American study group AHOPCA reported a 5-yearEFS of 61% with COPP with or without ABV and without RT acrossall stages. Abandonment of therapy was the major factor affecting theEFS rate, and substantial myelosuppression, especially for high-riskpatients, made this regimen difficult to administer (Table 2).26 In aneffort to reduce abandonment of therapy, AHOPCA switched to amodified Stanford V regimen in 2004. Because preliminary resultssuggested no improvement in EFS rates, in 2009, AHOPCA moved toOEPA-COPDAC chemotherapy for this patient group (AppendixTable A1).43,71 AHOPCA, GATLA, and other South American insti-tutions are now sharing the same protocol, which uses ABVD forlow- and intermediate-risk patients and OEPA-COPDAC foradvanced-stage HL. A response-adapted approach is used to prescribeRT. Given that the protocol is shared in Central and South America,but PET-CT (computed tomography) is only available in some of theSouth American sites, we will be able to compare the impact of ananatomic response assessment versus a combined anatomic and func-tional response assessment on the number of patients ultimately re-ceiving RT and the EFS rates of the respective approaches. Becauseprevention of abandonment and treatment-related deaths are othermajor challenges in low- and middle-income countries, the CAYAHL

platform facilitates problem solving and improving the survivalof patients.

STANDARDIZING THE DEFINITIONS FOR FDG-PET EVALUATION

FDG-PET images are currently interpreted visually, which is subject tohigh interobserver variability,72 and should therefore be centrally re-viewed within a clinical trial for quality assurance. The five-pointDeauville score, currently the widely used evaluation standard,73 re-lates the liver and mediastinum FDG uptake to the residual tumoruptake at an early response time point. The specific Deauville cutoffthat defines adequate or inadequate response depends on the time ofassessment and intensity of the chemotherapy regimen. Therefore, thecomplete metabolic FDG-PET response for assessment of early re-sponse in trials using intensive treatment regimens is now defined asDeauville 1 to 3.74,75 For assessment of late response, Deauville scoresof 3 or higher are considered FDG-PET positive, because this thresh-old may indicate residual tumor after chemotherapy. This strategy hassuccessfully been applied in the German Hodgkin Study Group HD15trial.76 The definition of FDG-PET positivity by the older Interna-tional Harmonization Project score, using the mediastinal blood pooland residual node size for reference, corresponds to a Deauville scoreof less than 3.77

Table 3. Summary of Recent Radiotherapy Reduction or Elimination Strategies in Pediatric and Adult Hodgkin Lymphoma Study Groups

Risk Group AHOPCA COG EuroNet-PHL C2-TrialSt Jude–Stanford–Dana

Farber Consortium EORTC GHSG

Low CR after 4 �ABVD: none

CR after cycle 3:none

AR at ERA: none CR: none � DV3 after 2 �ABVD: none

All: 30 Gy INRT

� CR after4 � ABVD: 20Gy IFRT

� CR: IFRT 21Gy

IR at ERA (� DV4):mIFRT 19.8 Gy

� CR: 25 Gy TFRT � DV3 after 2 �ABVD: 30 GyINRT

Intermediate CR after 6 �ABVD: none

RER after cycle 2,CR after cycle4: none

AR at ERA: none CR: 15 Gy IFRT All: 30 Gy INRT All: 30 Gy INRT

� CR after6 � ABVD: 20Gy IFRT

RER after cycle2, � CR aftercycle 4: 21 GyIF

IR at ERA (� DV4):randomized:standard cht: mIFRT19.8 Gy � 10 Gyboost to LRA �DV3-positive sites;intensified cht: 30Gy to LRA � DV3-positive sites only

� CR: 25 Gy IFRT

SER after cycle 2:21 Gy IF

High CR after 2 �OEPA 4 �COPDAC: 20Gy IFRT

RER: sites ofinitial bulk21Gy

AR at ERA: none CR after 2 � AEPA:none

Like GHSG 30 Gy INRT to LRA (� DV3)-positive sites only, noirradiation of extranodalsites

� CR after2 � OEPA 4 �COPDAC: 25Gy IFRT

SER: PET-positivesites and/orany site � 2.5cm after cycle 2

IR at ERA (� DV4):randomized:standard cht: mIFRT19.8 Gy � 10 Gyboost to LRA �DV3-positive sites;intensified cht: 30Gy to LRA � DV3-positive sites only

� CR after cycle 2 �AEPA: 25 Gy TFRT

Abbreviations: ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; AEPA, Adcetris (brentuximab vedotin), prednisone, etoposide, doxorubicin; mIFRT, modifiedinvolved-field radiotherapy; AHOPCA, Central American Association for Pediatric Hematology/Oncology; AR, adequate response after two cycles of initial OEPAchemotherapy (ie, PET negative [� DV4; ie, DV1-3]) and at least 50% volume reduction in bulk site; cht, chemotherapy; COG, Children’s Oncology Group; COPDAC,cyclophosphamide, vincristine, prednisone, dacarbazine; CR, complete remission; DV, Deauville score for PET response assessment;74 EORTC, EuropeanOrganisation for Research and Treatment of Cancer; ERA, early response assessment after two cycles of initial OEPA chemotherapy; EuroNet-PHL, EuropeanNetwork for Pediatric Hodgkin Lymphoma; GHSG, German Hodgkin Study Group; IFRT, involved-field radiotherapy; INRT, involved-node radiotherapy; IR, inadequateresponse after two cycles of initial OEPA chemotherapy (ie, PET-positive � DV4 or � 50% volume reduction in bulk site; LRA, late response assessment after allchemotherapy; OEPA, vincristine, prednisone, etoposide, doxorubicin; PET, positron emission tomography; RER, rapid early responder; SER, slow early responder;TFRT, tailored-field radiotherapy.





In 2014, Hasenclever et al78 reported the quantitative PET evalu-ation methodology to quantify the Deauville score. This method pro-vides a semiautomatic quantification for early FDG-PET response inHL and extends the ordinal Deauville scores to a continuous scale.Deauville categories correspond to certain qPET values. Thresholdsbetween normal and abnormal response can be derived from thedistribution of qPET values in a patient cohort. In the EuroNet-PHL-C1 trial, a certain qPET value after two cycles of OEPA chemo-therapy helped differentiate an abnormal response with highsensitivity. Total tumor glycolytic or metabolic volume methods arealso being investigated in pediatric HL.79

FDG-PET–guided response adaptation is being increasinglyused in pediatric HL. Figure 1 exemplifies how the concepts of re-sponse evaluation may be interpreted differently by different studygroups, thereby affecting further therapy modifications. For the cur-rent EuroNet-PHL-C2 trial, the definitions for PET response will bechanged to a higher threshold for PET positivity (Deauville 4) with theaim of increasing the percentage of patients in whom RT can beeliminated more than 50%. Accordingly, the patient shown in Figure1 will not receive RT in the future.

Chemotherapy intensification will be one tool used to compen-sate for the elimination for RT. In the COG AHOD0031 trial, thechemotherapy response for the patient shown in Figure 1 would havebeen interpreted as non-CR (ie, � 80% reduction) by two-dimensional anatomic response assessment, which would have alsoprompted IFRT after completing chemotherapy. The PET findingsafter two cycles of chemotherapy were visually assessed and docu-mented, but in contrast to the EuroNet-PHL-C1 trial, they were notused to make further treatment decisions. The comparability of defi-nitions for PET response and the varied use of CT criteria acrosscooperative trial groups remains an important source of controversy.

IMPROVING THE COMPARABILITY OF CLINICAL TRIAL RESULTS

To accurately compare the results of different trials, it is essential toconfirm that equivalent criteria are used for staging, treatment alloca-tion, and response assessment. Patients with HL are staged accordingto the Ann Arbor classification with or without the Cotswolds modi-fication.80 These criteria were defined in the 1960s and were based onclinical, surgical, and two-dimensional imaging modalities, whereasmodern staging systems rely exclusively on anatomic cross-sectionalimaging (CT-MRI [magnetic resonance imaging]), mostly in combi-nation with functional scans (PET-CT or PET-MRI). This may resultin a trend toward allocating patients to higher disease stages andconsequently higher risk groups because of more refined imagingtechnologies and lead to overtreatment of some patients. However,risk stratification and treatment group allocation differ widely notonly between adult and pediatric cooperative group trials but alsoamong the major pediatric HL study groups, and sometimes evenwithin the same group between generations of trials (Figure 2). Moststudy groups perform quality assurance through a central multidisci-plinary reference board for oncology, radiology, nuclear medicineimaging, and RT within their trial series. Quality assurance offeredthrough central reference and consultation centers can improve PFSrates by 10%.81 The Pediatric Hodgkin Network, a Web-based imagedata exchange tool, has been established for quality assurance in theEuroNet-PHL trials for European and extra-European countries.82,83

The SEARCH Effort for CAYAHL began in Arlington, Virginia,in 2011, and continued in Cologne in 2013 and Berlin in 2014. Firstresults on issues related to staging harmonization were presented inMay 2014 during the Second International Symposium on CAYAHL(2-ISCAYAHL 2014) in Berlin.48,49 Leaders of major pediatric HLconsortia from both sides of the Atlantic spearhead this ongoing effort.

Table 4. Systematic Radiotherapy Reduction and Elimination Strategies in the DAL/GPOH-HD/EuroNet-PHL Trials

TrialPatients

(No.) RT Indication

Standard Dose (Gy) and FieldEFS, %(years) OS (years)TG1 TG2 TG3

DAL-HD 78 170 All patients 36-40 EF 36-40 EF 36-40 EF 89% (4) 91% (5)1978-1981DAL-HD 82 203 All patients 35 IF 30 IF 30 IF 96% (3) 95% (5)1982-1984 5� 5�

DAL-HD 85 98 All patients 35 IF 30 IF 30 IF 74% (2) 98% (5)1985-1986 5� 5�

DAL-HD 87 196 All patients 35 IF 25 IF 30 IF 85% (7) 97% (7)1987-1990 5-10� 5�

DAL-HD 90 574 All patients 30 IF 25 IF 20 IF 90% (5) 98% (5)1990-1995 5� 5-10� 10-15�

GPOH-HD 95 925 All patients not in CR at end ofchemotherapy

20 mIF† 20 mIF 20 mIF 85% (10) 96% (10)1995-2001 10-15� 10-15� 10-15�

GPOH-HD 2002 573 All patients except TG1 in CR 20 mIF 20 mIF 20 mIF 89% (5) 97% (5)2002-2005 10-15� 10-15� 10-15�

EuroNet-PHL-C1 2110 Only patients with PET Deauville score� 3 after cycle 2 � OEPA

20 mIF 20 mIF 20 mIF Not yetevaluated

Not yetevaluated2007-2013 10� 10� 10�

Abbreviations: CR, complete remission (� 95% reduction of initial nodal volume and � 2 mL residual volume in any initially involved nodal site); EF, extended field;EFS, event-free survival; IF, involved field; mIF, modified involved field; OS, overall survival; PET, positron emission tomography; RT, radiotherapy; TG1, treatmentgroup 1 (stages IA, IB, IIA); TG2, treatment group 2 (stages IAE, IBE, IIAE, IIB, IIIA); TG3, treatment group 3 (stages IIBE, IIIB, IVA, IVAE, IVB, IVBE).

�Boost: If � 75% volume reduction or � 50 mL (DAL-HD90, GPOH-HD95) or � 100 mL (GPOH-HD 2002, EuroNet-PHL-C1) residual mass in any initially involvednodal site.†Modified involved field: Lateral margins of radiation fields depend on residual tumor extension after all chemotherapy.

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The harmonization process aims at higher comparability of treatmentresults among study groups and a more meaningful interpretation ofprognostic factors, but it may require continuous updating. Harmo-nization is an ever-dynamic process, but it is indispensable for intro-ducing new drugs and novel therapies in global trials.

EVALUATING TREATMENT FOR RARE ORUNIQUE HISTOPATHOLOGIES

The recognition of nodular lymphocyte-predominant HL (nLPHL) asa distinct entity by the WHO84 has generated interest in testing differ-ent treatment approaches for cHL and nLPHL. Children with nLPHLhave an OS of approximately 100%, and nLPHL is frequently found asa localized, early-stage disease. A meta-analysis of French, UnitedKingdom, and German trial series showed that surgery alone was afeasible option for localized disease, and yielded a long-term relapse-free survival of 67%.85 COG AHOD03P1 prospectively evaluated 52pediatric patients with stage I single-node disease treated with surgeryalone. Twelve patients who had stage IA relapse went on to receivechemotherapy and had a 3-year OS of 100%; none of the patientsrequired radiation.41 For nLPHL patients with incomplete resection,anthracycline-free chemotherapy combinations may be more effica-cious than RT-only approaches, such as those used in adult patients.86

In a retrospective case series, Shankar et al87 reported a 3-year freedomfrom treatment failure of 74% and OS of 100% for patients receivingcyclophosphamide, vinblastine, and prednisone chemotherapy. Onlypatients who did not at least achieve an unconfirmed CR (CRu;� 25% of the initial diagnostic nodal volume and � 2 mL) weretreated with more intensive chemotherapy. In the prospectiveAHOD03P1 trial, 137 low-risk patients receiving three cycles of doxo-rubicin, vincristine, prednisone, and cyclophosphamide had a 4-yearEFS of 88% and a 4-year OS of 100%. Only 11 patients did not achieveCR with this chemotherapy combination and required IFRT.41 In alarge retrospective report on 394 adult patients with nLPHL treated oncHL studies with a combination of chemotherapy and RT regimens,the relapse rate was not different between nLPHL and cHL patients.88

In contrast, the entity gray zone lymphoma (GZL), as defined bythe WHO,89 is a disease with intriguing features but lacking standardtreatment approaches. The features of GZL are intermediate betweenthose of cHL and diffuse large B-cell lymphoma or primary mediasti-nal B-cell lymphoma or between nLPHL and T-cell–rich B-cell lym-phoma or other variants. In a retrospective analysis, distinct histologicpatterns of nLPHL in adults have been correlated to prognostic fac-tors.90 GZL, a rare entity, has been successfully treated either accordingto protocols for cHL or mature B-cell non–Hodgkin lymphoma, de-pending on whether the diagnosis was made at initial presentation orat the time of relapsed or progressive disease. A preliminary anal-ysis of the German HL and N-HL registries42 revealed that pediat-ric patients with GZL were treated with either standard HLregimens, such as OEPA-COPDAC with or without RT, or accord-ing to intensive regimens for primary mediastinal B-celllymphoma, such as dose-adjusted etoposide, prednisone, cyclo-phosphamide, and doxorubicin plus rituximab.91 For successfullytreating such rare entities, establishing a proper histopathologicdiagnosis, including confirmation by expert pathology review, is of

A

B

Fig 1. (A) Fused [18F]fluoro-deoxy-glucose (FDG) positron emission tomog-raphy (PET) computed tomography images and (B) nonfused PET images ofcorresponding coronal (upper panels) and transversal (lower panels) slices atinitial diagnosis (left) and at response assessment after two cycles ofintensive chemotherapy (right) for a 15-year-old patient with classical Hodgkinlymphoma. The blue arrows in the right panels indicate a small residual masswith slightly enhanced FDG uptake after two cycles of chemotherapy. Thevisual PET assessment was performed by five independent and specializednuclear medicine physicians. Deauville (DV) criteria assessment varied fromDV2 to DV4. Three experts assessed PET positivity as DV3, which wasconsidered positive during the European Network for Pediatric HodgkinLymphoma Group trial C1 and was the basis for involved-field radiotherapyadministration. In addition, the patient received a radiation boost to theresidual mediastinal mass, which showed an anatomic volume reduction ofless than 75%. The semiautomatic quantification of the residual PET signalresulted in a quantified PET value of 1.26, which also corresponded to DV3.78

PET images courtesy of Lorraine Wilson, MD, consultant in nuclear medicine,Blackrock Clinic, Dublin, Ireland.





utmost importance. Combined efforts for harmonization of diag-nostic criteria across pediatric lymphoma study groups are re-quired to facilitate global trials on these rare entities.

NEW AGENTS

In the last decade, efforts have focused on studying new drugs andcompounds targeting epitopes or signaling pathways of the Hodgkinand Reed/Sternberg cells or the tumor microenvironment in relapsedor refractory patients. Targeting the B-cell receptor–dependent nu-clear factor-�B pathway with compounds such as bortezomib, a pro-teasome inhibitor that has favorable effects in vitro, has not proveneffective in phase I and II trials.92,93 A pediatric trial is currentlyevaluating panobinostat, a histone deacetylase inhibitor, in patientswith relapsed HL, although this agent is likely more active when usedin combination with other agents.94

CD30, a member of the tumor necrosis factor-� receptor family,which is expressed almost exclusively on HL cells, has been an attrac-tive target for antibody therapy. Initial attempts of treatment withnaked CD30 antibodies were unsuccessful but later improved whenthe antibody was coupled with radioactive compounds or cytotoxicdrugs. Patients with relapsed and refractory HL administered bren-tuximab vedotin, an antibody–drug conjugate with the antitubulinagent monomethyl auristatin E, had favorable overall responserates.95,96 Long-term results have shown that brentuximab vedotinmonotherapy as second- or third-line treatment has not proven cura-tive in patients with multiple relapses; the results of trials with thiscompound in combination with conventional chemotherapy regi-

mens are not yet available. According to the principle of a mosteffective first hit strategy, brentuximab vedotin has now been intro-duced into first-line treatment in adults97 and children with HL. In anongoing study of the St Jude–Stanford–Dana Farber consortium,brentuximab vedotin has replaced vincristine in the OEPA-COPDACregimen for high-risk patients98 with the aim of further reducing thenumber of high-risk patients who require RT. With the same aim, theCOG is initiating a random assignment phase III trial to evaluatethe efficacy of brentuximab vedotin in combination with AVE-PCchemotherapy.99 This is part of the overall treatment strategy forpediatric HL to identify highly effective chemotherapy regimens thatminimize late effects and reduce the need for RT for the majorityof patients.

Nivolumab is another new agent currently under investigationthat seems to be highly efficacious in relapsed and refractory patientswith HL. This antibody may block the programmed death-1 pathwaythought to be used by Hodgkin and Reed/Sternberg cells to evadeimmune detection. Early results are encouraging and suggest thatnivolumab has an exceptionally safe profile,100 thereby making it anattractive candidate for early evaluation in pediatric patients.

FUTURE DIRECTIONS AND CONCLUSIONS

Increasing our knowledge about the genetic risk factors associatedwith long-term sequelae can lead to the development of treatmentstrategies that consider the individual’s genetic risk. Recently, Maet al101 showed that genetic polymorphisms of FGFR2 correlate

Study Group Risk IA IB IIA IIB IIIA IIIB IVA IVB

COG

AHOD0431 – Low

AHOD0031 – Intermediate EX

EX

AHOD0831 – High

EuroNet-PHL-C1*

TG1– Low

TG2 – Intermediate E

RF E

RF E

RF

TG3 – High E E

EuroNet-PHL-C2

TL1 – Low

TL2 – Intermediate E

RFE

RF E

RF

TL3 – High E E

Pediatric Hodgkin Consortium

HOD99/HOD08 – Low < 3 ns

HOD05 – Intermediate E

mX E

mX

HOD99/HLHR13 – High

Fig 2. Variation in risk stratification across pediartic Hodgkin study groups and protocols. E, extranodal extension; X, bulky disease (peripheral � 6 cm and mediastinalbulk); mX, mediastinal bulk (� 0.33 mediastinal to thoracic ratio); ns, nodal site; TG, treatment group; TL, treatment level; RF, risk factors: erythrocyte sedimentationrate � 30 mm/hour and/or bulk � 200 mL. (*) EuroNet-PHL-C1 was amended in 2012: Low-risk (TG1) patients with ESR � 30 mm/hour and/or bulk � 200 mL weretreated in TG2 (intermediate risk).

Mauz-Körholz et al




significantly with the risk of breast cancer after mediastinal irradi-ation. In addition, estrogens may induce oncogenic effects throughFGFR2 signaling.102 Furthermore, decreased basic expression ofPRDM1, a tumor suppression gene, is significantly associatedwith radiation-induced secondary cancer after childhood HL.103

Radiation-induced repression of the proproliferative gene Myc invitro is enhanced by high expression of PRDM1. Visscher et al104

recently showed that variants of the human concentrative nucleo-side transporter SLC28A1 as well as the cassette transporter genesABCB4 or ABCC1 are significantly associated with an increasedrisk of anthracycline-induced cardiotoxicity.

In the future, HL patients at high risk for anthracycline-inducedcardiotoxicity may be treated with combined-modality strategies thatlimit anthracyclines, whereas patients at high risk for RT-inducedsecond malignancies may benefit more from intensive chemotherapyregimens that spare RT. Multinational research programs that cancorrelate cumulative long-term risk factors with genetic polymor-phisms are required to investigate the feasibility and benefits of genet-ically stratified therapy.

Between the end of the 1970s and the early 1990s, combined-modality treatment approaches using chemotherapy with fairly lowcumulative doses of anthracyclines and RT yielded high cure rates inchildren and adolescents with HL.1,28,29,105,106 Since then, the indica-tion for a stepwise reduction of RT has been evaluated by using arisk-stratified, response-adapted strategy according to anatomic andmetabolic response criteria. Thus, regimens with quite intensive buttoxic drug doses can compensate for RT and lead to excellent EFSrates, but they may result in lower long-term OS rates as demonstratedin a trial series on adults.107 Future efforts in the treatment of bothadults and children with HL should focus on developing personalized

therapies, considering individual risk factors, and introducing newdrugs with a safe profile that target specific HL pathways.

The progress and, consequently, the success in the treatment ofpediatric HL have largely been achieved through collaborative effortsof national and multinational study groups. The ultimate goal forcollaborative efforts has always been the reduction of treatment bur-den and the maintaining of high cure rates. In the future, noveltherapies and targeted compounds should be studied thoroughly inongoing collaborations to develop the most effective but even lesstoxic treatments. Because HL affects young people in the prime oftheir lives, it is important to efficiently control it. The effect of latetoxicities of these treatments needs to be limited, as they have a signif-icant effect on society as a whole.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST

Disclosures provided by the authors are available with this article atwww.jco.org.

AUTHOR CONTRIBUTIONS

Conception and design: Christine Mauz- Körholz, Monika L. Metzger,Kara M. Kelly, Cindy L. Schwartz, Dieter KörholzAdministrative support: Dieter KörholzCollection and assembly of data: All authorsData analysis and interpretation: All authorsManuscript writing: All authorsFinal approval of manuscript: All authors

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AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST


The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships areself-held unless noted. I � Immediate Family Member, Inst � My Institution. Relationships may not relate to the subject matter of this manuscript. For moreinformation about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.

Christine Mauz-KörholzNo relationship to disclose

Monika L. MetzgerNo relationship to disclose

Kara M. KellyNo relationship to disclose

Cindy L. SchwartzNo relationship to disclose

Mauricio E. CastellanosNo relationship to disclose

Karin DieckmannNo relationship to disclose

Regine KlugeNo relationship to disclose

Dieter KörholzNo relationship to disclose

Mauz-Körholz et al

© 2015 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY



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http://jco.ascopubs.org/site/ifc

Appendix

Table A1. Summary of Recently Completed but Not Yet Evaluated, Ongoing, and Future First-Line Treatment Trials in Pediatric ClassicalHodgkin Lymphoma

Study Risk Design Chemotherapy� Radiation Comments

Children’s Oncology Group(COG) trials

AHOD0431 Low Non randomized,response-based RTallocation

3 � AVPC CR: none Study completed, resultsunder evaluation andsuggest that CR statusafter three cycles maynot optimally identifypatients in whom RTcan be omitted. EarlyPET response (after onecycle) appears to havesignificant prognosticimplications

� CR: 21 Gy IF

AHOD0831 High Non randomized,response-based therapyallocation

RER: 4 � ABVE-PCSER: 2 � ABVE-PC � 2 � IV � 2ABVE-PC

RER: sites of initialbulk 21 Gy SER:PET-positivesites, any site� 2.5 cm

Study completed, resultsunder evaluation

AHOD1331 High Randomized chemotherapyallocation withresponse-based RT

Standard: 5 �ABVE-PCExperimental:5 � Bv-AVE-PC

bulky mediastinalmass, PET-avidlesions aftercycle 2, 21 GyISRT

Randomized chemotherapyallocation withresponse-based RT

European Network forPediatric HodgkinLymphoma (EuroNet-PHL) trials

EuroNet-PHL- C1(recently completed)

Low (TG1) Nonrandomized response-based RT

All: 2 � OEPA AR: none; IR: 19.8Gy IF


Intermediate(TG2)

Randomized chemotherapyallocation withresponse-based RT

2 � OEPA � 2 �COPP/COPDAC

AR: no RT IR: 19.8Gy IF


High (TG3) Randomized chemotherapyallocation withresponse-based RT

2 � OEPA � 4 �COPP/COPDAC

AR: none; IR: 19.8Gy IF


EuroNet-PHL C2(projected to openSpring 2015)

Low (TL1) Nonrandomized response-based therapy allocation

AR: 2 � OEPA �1 � COPDAC-28IR: 2 � OEPA

AR: none; IR: 19.8Gy IF

Patients in AR at earlyresponse assessmentreceive one additionalcycle of COPDAC;patients in IR receivestandard IFRT (19.8 Gyto IF)

Intermediate(TL2)

Randomized chemotherapyallocation and response-based RT

2 � OEPA � 2 �COPDAC-28/ 2 �DECOPDAC-21

AR: none; IR/LRA:COPDAC: 19.8Gy IF � 10 Gyboost to LRAPET-positivesitesDECOPDAC: 30Gy to LRA PET-positive sites

TL2 patients are randomlyassigned betweenstandard (COPDAC) andintensified (DECOPDAC)chemotherapy; lateresponse assessment atthe end of allchemotherapy is onlydone for patients withIR after OEPA

High (TL3) Randomized chemotherapyallocation and response-based RT

2 � OEPA � 4 vCOPDAC-28/ 4 �DECOPDAC-21

AR: none; IR/LRA(COPDAC): 19.8Gy IF � 10 Gyboost to LRAPET-positivesites;(DECOPDAC):30 Gy to LRAPET-positivesites

TL3 patients are randomlyassigned betweenstandard (COPDAC) andintensified (DECOPDAC)chemotherapy; lateresponse assessment atthe end of allchemotherapy is onlydone for patients withIR after OEPA

(continued on following page)


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Table A1. Summary of Recently Completed but Not Yet Evaluated, Ongoing, and Future First-Line Treatment Trials in Pediatric ClassicalHodgkin Lymphoma (continued)

Study Risk Design Chemotherapy� Radiation Comments

St Jude–Stanford–DanaFarber consortiumtrials

HOD99 (recentlycompleted)

High Nonrandomized, response-based RT

Stanford V CR: 15 Gy IF;� CR: 25 Gy IF


HOD05 (recentlycompleted)

Intermediate Nonrandomized, response-based RT



HOD08 (ongoing) Low Nonrandomized, response-based RT

Reduced Stanford V CR: none; � CR:25 Gy TF

Ongoing trial

HOD13 (ongoing) High Nonrandomized, response-based RT

2 � AEPA � 4 �CAPDAC

CR: none; � CR:25 Gy TF

Ongoing trial

AHOPCA consortium trialsLH 2009 Low Nonrandomized, response-

based RT4 � ABVD CR: none; � CR:

25 Gy IFPatients in CR after four

cycles do not receiveRT

Intermediate Nonrandomized, response-based RT

6 � ABVD CR: none; � CR:25 Gy IF

Sites in CR after twocycles of ABVD do notreceive RT



Study completed, resultsunder evaluation butappear to not beacceptable atapproximately only 60%event-free survival


2 � OEPA � 4 �COPDAC

CR: 20 Gy IF;� CR: 25 Gy IF

Ongoing trial, aim toimprove event freesurvival compared tohistorical control withStanford V

Abbreviations: ABVE-PC, doxorubicin 50 mg/m2, bleomycin 15 IU/m2, vincristine 2.8 mg/m2, etoposide 375 mg/m2; prednisone 280 mg/m2, cyclophosphamide1,200 mg/m2; AEPA, Adcetris (brentuximab vedotin) 3.6 mg/m2, prednisone 900 mg/m2, etoposide 625 mg/m2, doxorubicin 160 mg/m2; AR, adequate response aftertwo cycles of initial OEPA chemotherapy (ie, PET(�) and at least 50% volume reduction in all initially involved sites; Bv-AVE-PC, brentuximab vedotin 1.8 mg/kg,doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, etoposide 375 mg/m2, prednisone 280 mg/m2, cyclophosphamide 1,200 mg/m2; CAPDAC, cyclophosphamide 1,000mg/m2, Adcetris (brentuximab vedotin) 2.4 mg/m2, prednisone 600 mg/m2, dacarbazine 750 mg/m2; COPDAC-28 (28-day cycle), cyclophosphamide 1,000 mg/m2,vincristine 3.6 mg/m2, prednisone 600 mg/m2, dacarbazine 750 mg/m2; CR, complete remission; DECOPDAC-21 (21-day cycle), doxorubicin 25 mg/m2, etoposide300 mg/m2, prednisone 320 mg/m2, dacarbazine 750 mg/m2; IF, involved field; IR: inadequate response after two cycles of initial OEPA chemotherapy (ie,PET-positive and no progression in at least one initially involved site; ISRT, involved-site radiotherapy; IV, ifosphamide 12,000 mg/m2, vinorelbine 50 mg/m2; OEPA,vincristine 5.4 mg/m2, prednisone 900 mg/m2, etoposide 625 mg/m2, doxorubicin 160 mg/m2; PET, positron emission tomography; RER, rapid early responder; SER,slow early responder; Stanford V, doxorubicin 125 mg/m2, vinblastine 30 mg/m2, bleomycin 30 IU/m2, vincristine 8.4 mg/m2, etoposide 360 mg/m2, prednisone 3,000mg/m2, cyclophosphamide 1,800 mg/m2; TF, tailored field.

�All drug doses are shown as cumulative doses per cycle, except for Stanford V, for which cumulative drug doses for the entire regimen are given.

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Pediatric Hodgkin Lymphoma...Summary of Recently Evaluated First-Line Treatment Trials in Pediatric Classical Hodgkin Lymphoma Study Risk Design No. Chemotherapy Radiation Key Findings